This protocol is designed to study the natural history and epidemiology of hepatitis C virus (HCV) infection in an asymptomatic blood donor population found to be anti-HCV positive at the time of routine blood donation. Thus far, 560 subjects have been enrolled including 305 recombinant bioimmunassay (RIBA) positives, 143 RIBA indeterminates, and 112 RIBA negative controls. The accrued data have been published recently (New Engl J Med 1996; 334:1691) and can be summarized as follows: Characteristics of HCV-infected donors compared with controls were younger, African-American, and had a lower education level. Independently associated risk factors for HCV were transfusion, intravenous drug use (IVDU), cocaine snorting, sexual promiscuity, and being male with pierced ears. Although it was anticipated that IVDU would be a risk factor, it was a major surprise to find that 42 percent of RIBA positive volunteer blood donors admitted to having used intravenous drugs at some point in their lives, generally 10 or more years before the donation. Another major surprise was the strong independent association between cocaine snorting and HCV positivity. Shared paraphernalia for snorting accompanied by frequent cocaine-related epistaxis may serve as a covert vehicle for parenteral viral transmission. Eighty-six percent of RIBA positive donors were viremic, confirming the persistent nature of this agent. In contrast, 13 percent of subjects appeared to have recovered from HCV infection as evidenced by repeatedly negative polymerase chain reaction for HCV RNA and by persistently normal alanine aminotransferase. Sixty-six percent had biochemical evidence of liver disease, and 86 percent of those biopsied had a severe histologic lesion despite prolonged infection despite an association evidence of mild to moderate chronic hepatitis. However, only 6 percent had a severe histologic lesion despite prolonged infection. Despite an association with sexually promiscuous practices, when we tested the direct partners of HCV- infected individuals, we found no evidence for HCV's sexual transmission.